Evaluation of an Innovative Therapeutic to Prevent and/or Delay the Progression of ALI/ARDS in a Non-Human Primate Model
Abstract
Acute lung injury (ALI) and its more severe manifestation, acute respiratory distress syndrome (ARDS), are severe forms of lung edema that precede respiratory failure and multiple organ dysfunction. ARDS affects over 3 million people globally and approximately 200,000 people in the U.S. each year. ALI/ARDS can result from direct (inhalation of toxic agents, pneumonia, infection) or indirect (sepsis, blast, or burn) injuries to the lung. ALI/ARDS is an accumulation of fluid in the lungs that results from the destruction of the layer of interconnected cells separating inspired air from fluid-filled tissues, termed the pulmonary barrier. Once ALI has progressed to ARDS, the only treatment options are invasive critical care procedures including mechanical ventilation and extracorporeal membrane oxygenation (ECMO). Despite the availability of state-of-the-art critical care medicine, ARDS mortality remains ~40%. Exposure to burn pits, blast and polytraumatic injuries, and inhalation of biological or chemical agents place U.S. Service Members at high risk for injuries that result in the development of ALI/ARDS. Veterans are similarly vulnerable due to high prevalence of conditions including pancreatitis, alcoholism, and pneumonia that predispose this population to develop ALI/ARDS. For patients that do recover from ARDS, poor pulmonary function and neurocognitive deficits are often lifelong complications. Compounding the dismal mortality associated with ARDS, the use of mechanical ventilation is limited by the availability of intensive care unit (ICU) beds, specialized ventilator equipment, and health care workers trained to use them. There is a critical unmet clinical need for an effective therapeutic that prevents and/or delays the progression of ALI/ARDS. There are currently no U.S. Food and Drug Administration (FDA)-approved therapies on the market for ALI/ARDS. Furthermore, no therapeutics in development directly target intercellular junctions to prevent the pathological loss of pulmonary barrier function that underlies ARDS. The transmembrane protein Connexin43 (Cx43) has well-defined roles in inflammation, tissue regeneration, and scarring. FirstString Research has bioengineered a cell-permeable peptide therapeutic, termed aCT1, that modulates Cx43 signaling to strengthen intercellular junctions, dampen inflammation, and promote an effective response to tissue injury. FirstString has formulated aCT1 into an Investigational New Drug (IND)-approved (#074836) topical gel (Granexin) that is currently in late-stage, pivotal trials for cutaneous radiation injury, cutaneous scarring, and thermal burns. Across numerous preclinical studies and six clinical trials in several injury indications, aCT1’s ability to stabilize intercellular junctions has been proven to reduce inflammation and promote an effective response to tissue injury. aCT1 would represent the first therapeutic product targeting the molecular and cellular mechanisms of ALI/ARDS, promoting barrier integrity, and limiting inflammation to prevent and treat this complex respiratory complication. Treatment of ALI/ARDS patients with aerosolized aCT1 is expected to preserve pulmonary barrier integrity and dampen inflammation. Preventing development of acute respiratory failure in ALI/ARDS patients will lessen the need for resource intensive mechanical ventilation and dramatically improve survival. Existing IND-enabling preclinical and clinical safety data for aCT1 enable a rapid path to its clinical use in military Service Members and civilians. In direct response to the FY21 PRMRP Expansion Award Respiratory Health Topic Area, Area of Encouragement Development and/or testing of novel and/or innovative treatments including precision medicine approaches, to prevent, or delay progression of, ALI/ARDS, the proposed research project aims to evaluate efficacy of aerosolized aCT1 in preventing and treating ALI/ARDS. We will also optimize the aCT1 inhalation solution formulat
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2211066
Entities
People
- Meghan Bowler
Organizations
- United States Army